The goal of this work is to investigate occupational causes of Parkinson's disease (PD). The long-term neurological toxicity of occupational solvent exposure is poorly understood. Although acute Parkinsonism may rarely result from accidental high dose solvent exposures, these cases are clinically and pathologically distinct from PD. In contrast, epidemiologic associations of occupational exposures with typical PD are inconsistent. In 2008 Gash et al reported a cluster of 3 PD patients who had been exposed to the solvent trichloroethylene (TCE) in a manufacturing plant. Preliminary work in our population-based analytic study (the TWINS study) found a significant 6-fold increased risk of PD associated with occupational TCE exposure. The chlorinated solvents tetrachloroethylene (PERC, perchloroethylene) and carbon tetrachloride (CCl4) were also associated. In addition, a recent TCE model in rodents strikingly recapitulates many of the features of PD, further supporting the biological relevance of these observations. Two major deficiencies limit current understanding of the role of TCE, PERC and CCl4 in PD. First, few prior studies assessed exposure to specific agents, instead considering solvent exposure as a single categorical variable. Because solvents encompass a huge range of disparate compounds, association with any particular agent is likely to be obscured using this approach. A second deficiency in our knowledge is the lack of concomitant investigation of genetic and environmental factors that may affect solvent-related toxicity. This study will focus on the relationship between the industrial solvents TCE, PERC and CCl4 and PD risk, and will simultaneously consider interactions with genetic and environmental factors. We will leverage existing data derived over 15 years of research in 1,250 subjects from two well-characterized PD case-control study populations that share uniform, standardized, highly detailed occupational-task-specific interview methods. We will apply unbiased exposure estimation methods in order to quantify lifetime exposures to TCE, PERC, and CCl4, and test associations with PD. Using a larger independent cohort (SEARCH); we will test our preliminary findings in the TWINS study. This work is essential in order to establish a causal association. In addition, using existing DNA samples from both TWINS and SEARCH, we will test for interaction between these solvents and 1) variants in genes encoding enzymes involved in their metabolism, and 2) PD-associated genes. We will also test for interaction of solvents and environmental risk factors. The health implications of this work are immense. Solvents are ubiquitous in industry, and even a modest increased risk could have an enormous impact on the frequency of PD in workers. This work is essential to advance our knowledge of the risk posed by solvents, and will provide a rational foundation for protection of the workforce from this incurable debilitating disease.